The human erythrocyte sugar transporter is also a nucleotide binding protein

Carruthers, Anthony; Helgerson, Amy L.

doi:10.1021/bi00447a011

Cited by 76 publications

(86 citation statements)

References 38 publications

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“…Taken together, the above data suggest that inactive Glut1 molecules at the plasma membrane are activated during mitochondrial inhibition. For instance, ATP allosterically inhibits Glut1 and therefore V max is increased when ATP levels are reduced (Carruthers and Helgerson, 1989). The latter might occur upon acute mitochondrial inhibition and trigger a compensatory increase in glucose uptake.…”

Section: Discussionmentioning

confidence: 99%

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

Liemburg-Apers

Wagenaars

Smeitink

et al. 2016

Journal of Cell Science

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Mitochondria play a central role in cellular energy production, and their dysfunction can trigger a compensatory increase in glycolytic flux to sustain cellular ATP levels. Here, we studied the mechanism of this homeostatic phenomenon in C2C12 myoblasts. Acute (30 min) mitoenergetic dysfunction induced by the mitochondrial inhibitors piericidin A and antimycin A stimulated Glut1-mediated glucose uptake without altering Glut1 (also known as SLC2A1) mRNA or plasma membrane levels. The serine/threonine liver kinase B1 (LKB1; also known as STK11) and AMP-activated protein kinase (AMPK) played a central role in this stimulation. In contrast, ataxiatelangiectasia mutated (ATM; a potential AMPK kinase) and hydroethidium (HEt)-oxidizing reactive oxygen species (ROS; increased in piericidin-A-and antimycin-A-treated cells) appeared not to be involved in the stimulation of glucose uptake. Treatment with mitochondrial inhibitors increased NAD + and NADH levels (associated with a lower NAD + :NADH ratio) but did not affect the level of Glut1 acetylation. Stimulation of glucose uptake was greatly reduced by chemical inhibition of Sirt2 or mTOR-RAPTOR. We propose that mitochondrial dysfunction triggers LKB1-mediated AMPK activation, which stimulates Sirt2 phosphorylation, leading to activation of mTOR-RAPTOR and Glut1-mediated glucose uptake.

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Section: Discussionmentioning

confidence: 99%

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

Liemburg-Apers

Wagenaars

Smeitink

et al. 2016

Journal of Cell Science

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“…When studying red cell "ghosts" (cytoplasm is replaced with saline by reversible hypotonic hemolysis), transport asymmetry is greatly diminished [V max and K m for uptake increase and approach V max and K m for exit (18)]. This is caused by the loss of cytoplasmic ATP, which allosterically modifies the catalytic properties of GLUT1 by binding reversibly to a GLUT1 ATP-binding site (10,16).…”

Section: Transport Kinetic Asymmetrymentioning

confidence: 99%

Will the original glucose transporter isoform please stand up!

Carruthers

DeZutter

Ganguly

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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185

190

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Monosaccharides enter cells by slow translipid bilayer diffusion by rapid, protein-mediated, cation-dependent cotransport and by rapid, protein-mediated equilibrative transport. This review addresses protein-mediated, equilibrative glucose transport catalyzed by GLUT1, the first equilibrative glucose transporter to be identified, purified, and cloned. GLUT1 is a polytopic, membranespanning protein that is one of 13 members of the human equilibrative glucose transport protein family. We review GLUT1 catalytic and ligand-binding properties and interpret these behaviors in the context of several putative mechanisms for protein-mediated transport. We conclude that no single model satisfactorily explains GLUT1 behavior. We then review GLUT1 topology, subunit architecture, and oligomeric structure and examine a new model for sugar transport that combines structural and kinetic analyses to satisfactorily reproduce GLUT1 behavior in human erythrocytes. We next review GLUT1 cell biology and the transcriptional and posttranscriptional regulation of GLUT1 expression in the context of development and in response to glucose perturbations and hypoxia in blood-tissue barriers. Emphasis is placed on transgenic GLUT1 overexpression and null mutant model systems, the latter serving as surrogates for the human GLUT1 deficiency syndrome. Finally, we review the role of GLUT1 in the absence or deficiency of a related isoform, GLUT3, toward establishing the physiological significance of coordination between these two isoforms. glucose transport; facilitated diffusion; major facilitator superfamily protein; bloodbrain barrier; placenta; diabetes; glucose transporter 1 deficiency syndrome; development MOST CELLS TRANSPORT SUGARS rapidly down the prevailing concentration gradient into or out of the cell. This equilibrative transport process is mediated by a family of sugar transporters called GLUTs. GLUT1 was the first glucose transporter isoform to be identified, purified (66, 132), and cloned (93) and is one of 13 proteins that comprise the human equilibrative glucose transporter family (63). GLUT1 is a membrane-spanning glycoprotein containing 12 transmembrane domains with a single N-glycosylation site, and its gene is located on chromosome 1 (1p35-31.3) (93). GLUT1 is expressed at the highest levels in the plasma membranes of proliferating cells forming the early developing embryo, in cells forming the blood-tissue barriers, in human erythrocytes and astrocytes, and in cardiac muscle (86). Having a catalytic turnover of ϳ1,200/s (115), glucose transporter 1 (GLUT1) provides an efficient pathway for cellular import and export of glucose. In addition, GLUT1 transports galactose and ascorbic acid (81,107). This review examines the catalytic properties, structure, molecular regulation, and physiology of GLUT1. GLUT1 CATALYTIC PROPERTIES Facilitated DiffusionThe cytoplasm of most cells equilibrates rapidly with nonmetabolizable extracellular sugars. This process is mediated by sugar transport proteins that catalyze unidirectional sugar up...

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“…Provided that the ratio V max /K m for exit = V max /K m for entry, the rate of glucose exit and entry will be identical at identical, subsaturating intra-and extracellular [Glc]. Glucose transport in cytosol-depleted human red cell ghosts is symmetric, that is V max and K m for D-glucose entry increase to match the equivalent parameters for exit (Carruthers, 1986;Carruthers and Melchior, 1983;Helgerson et al, 1989). In human erythrocytes, the GLUT1 activity is modulated by ATP, which interacts allosterically to transform the intrinsically symmetric carrier into an asymmetric carrier (Carruthers and Helgerson, 1989;Levine et al, 1998).…”

Section: Kinetics Of Glucose Transportmentioning

confidence: 99%

“…Glucose transport in cytosol-depleted human red cell ghosts is symmetric, that is V max and K m for D-glucose entry increase to match the equivalent parameters for exit (Carruthers, 1986;Carruthers and Melchior, 1983;Helgerson et al, 1989). In human erythrocytes, the GLUT1 activity is modulated by ATP, which interacts allosterically to transform the intrinsically symmetric carrier into an asymmetric carrier (Carruthers and Helgerson, 1989;Levine et al, 1998). Transport measurements in red cell ghosts show that the rate of net cellular export of 10 mmol/L glucose into saline containing 3 mmol/L glucose is inhibited 50% by intracellular ATP (i.e., when transport is asymmetric).…”

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confidence: 99%

Supply and Demand in Cerebral Energy Metabolism: The Role of Nutrient Transporters

Simpson

Carruthers

Vannucci

2007

J Cereb Blood Flow Metab

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703

749

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Glucose is the obligate energetic fuel for the mammalian brain, and most studies of cerebral energy metabolism assume that the majority of cerebral glucose utilization fuels neuronal activity via oxidative metabolism, both in the basal and activated state. Glucose transporter (GLUT) proteins deliver glucose from the circulation to the brain: GLUT1 in the microvascular endothelial cells of the blood-brain barrier (BBB) and glia; GLUT3 in neurons. Lactate, the glycolytic product of glucose metabolism, is transported into and out of neural cells by the monocarboxylate transporters (MCT): MCT1 in the BBB and astrocytes and MCT2 in neurons. The proposal of the astrocyte-neuron lactate shuttle hypothesis suggested that astrocytes play the primary role in cerebral glucose utilization and generate lactate for neuronal energetics, especially during activation. Since the identification of the GLUTs and MCTs in brain, much has been learned about their transport properties, that is capacity and affinity for substrate, which must be considered in any model of cerebral glucose uptake and utilization. Using concentrations and kinetic parameters of GLUT1 and -3 in BBB endothelial cells, astrocytes, and neurons, along with the corresponding kinetic properties of the MCTs, we have successfully modeled brain glucose and lactate levels as well as lactate transients in response to neuronal stimulation. Simulations based on these parameters suggest that glucose readily diffuses through the basal lamina and interstitium to neurons, which are primarily responsible for glucose uptake, metabolism, and the generation of the lactate transients observed on neuronal activation. Keywords: glucose and lactate; glucose transporter proteins; mathematical modeling; monocarboxylate transporters; neurons and astrocytes; substrate delivery and metabolism IntroductionThe central dogma of cerebral energy metabolism is that glucose is the obligate energetic fuel of the mammalian brain and the only substrate able to completely sustain neural activity (Siesjo, 1978). Furthermore, it has traditionally been assumed that the majority of cerebral glucose utilization fuels neuronal activity via oxidative metabolism, both in the basal and activated state (Sokoloff et al, 1977). Rates of cerebral blood flow directly relate to measurements of cerebral oxygen consumption, generating the concept of the 'flow-metabolism couple' (Sokoloff, 1976;Sokoloff et al, 1977). The introduction of neuroimaging techniques to study cerebral metabolism revealed an 'uncoupling' between cerebral oxygen consumption, blood flow, and glucose utilization during brain activation (Fox and Raichle, 1986; Fox et al, 1988), with the suggestion of regional stimulation of oxidative glycolysis during neuronal activation. The temporal relationship between the release of lactate and the onset of neuronal activation, the source of the lactate, that is neuronal or glial, and its subsequent diffusion and disposal are all matters of considerable debate. Initial studies by Prichard et al (1991) assu...

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The human erythrocyte sugar transporter is also a nucleotide binding protein

Cited by 76 publications

References 38 publications

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

Will the original glucose transporter isoform please stand up!

Supply and Demand in Cerebral Energy Metabolism: The Role of Nutrient Transporters

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